Intermediates for the production of imidazobenzodiazepines

ABSTRACT

Novel intermediates of the formula ##STR1## wherein X and Y are hydrogen, halogen or trifluoromethyl and R 1  is hydrogen or lower alkyl are presented. 
     Also disclosed is a process leading to the intermediates and their conversion to imidazobenzodiazepines, compounds of pharmacological activity.

This is a division of application Ser. No. 105,823, filed Dec. 20, 1979.

DESCRIPTION OF THE INVENTION

The present invention relates to novel intermediates of the formula##STR2## wherein X and Y are selected from the group consisting ofhydrogen, halogen and trifluoromethyl and R₁ is hydrogen or lower alkyl.

As utilized herein the term "halogen" shall mean all four forms thereof,i.e., chloro, bromo, iodo and fluoro.

As utilized herein the term "lower alkyl" shall mean straight orbranched chain hydrocarbon radicals of C₁ to C₇ length, preferably C₁ toC₄, e.g., methyl, ethyl, isopropyl, butyl, etc.

The novel intermediates and process of the present invention areillustrated in the following reaction scheme: ##STR3## wherein X and Yare as above, Z is halogen or a leaving group and R₁ is lower alkyl orhydrogen.

I→II

The starting material (ketone) of formula I is a known compound, see,for example, U.S. Pat. No. 3,141,890 wherein the compound is disclosed.

The starting material is reacted with a hydroxylamine salt, such as,hydroxylamine sulfate or hydrochloride in an inert hydrocarbon solvent,such as, a C₁ to C₆ alcohol or pyridine. The reaction temperature may bevaried from about 0° C. to about 200° C. with reflux temperature of theselected solvent as preferred.

Thereafter the resultant product is reacted with a lower alkyl ketone,such as, acetone, dimethyl ketone or diethyl ketone in the presence of acopper salt such as cupric sulfate or acetate or cuprous chloride. Thereaction solvent can be the lower alkyl ketone itself or inerthydrocarbon solvents such as methylene chloride, benzene, toluene or aC₁ to C₆ alcohol. The reaction temperature may range from about roomtemperature to reflux temperature with about 60° C. as preferred.

II→III

The dihydroquinazoline compound of formula II may thereafter be reactedwith water in the presence of a dilute strong acid, such as,hydrochloric, sulfuric, phosphoric or trifluoracetic acid to produce theβ-oxime. The reaction may be carried out at from about 0° C. to about80° C. with about room temperature as preferred. The compounds offormulas II and III are known compounds, see, for examle, U.S. Pat. Nos.3,509,145; 3,505,975 and 3,398,139 and articles in the Journal ofOrganic Chemistry, Vol. 30, 3959 (1965) and Journal of the AmericanChemical Society, Vol. 89, 332 (1967).

II OR III→IV

The compounds of formulas II or III may thereafter undergo an acidcatalyzed reaction with a compound of the formula ##STR4## wherein R₁ ishydrogen or lower alkyl and Z is halogen or a leaving group.

Suitable leaving groups include aryl or alkyl sulfonyl radicals, suchas, mesyl or tosyl.

Solvents suitable for the above reaction include inert organic solvents,such as, C₁ to C₆ alcohols, tetrahydrofuran and dimethylformamide.Reaction temperatures may range from about room temperature to about120° C. with reflux temperature of the particular solvent preferred.

IV→V

The quinazoline of formula IV is thereafter treated with a strong base,such as, an alkali metal hydroxide, alkoxide or amide, e.g., potassiumor sodium hydroxide, potassium or sodium butoxide or sodium amide.Suitable solvents include inert organic solvents, such as,tetrahydrofuran, C₁ to C₆ alcohols, dimethylformamide ordimethylsulfoxide. Reaction temperatures may range from about -10° C. toabout 100° C. with room temperature as preferred.

The compound of formula V is an intermediate in the preparation ofimidazobenzodiazepines. Examples 13 to 23 in the present specificationset forth a method of preparing such imidazobenzodiazepines which areuseful as sedatives, anxiolytics, muscle relaxants and anticonvulsantsbut are not a part of the present invention.

The present process provides a method utilizing well-known andinexpensive starting materials and thus is less costly than prior artprocesses. The process steps are simple to carry out and thus require nospecial equipment.

EXAMPLE 16-Chloro-2,2-dimethyl-4-(2-fluorophenyl)-1,2-dihydroquinazoline, 3-oxide

A mixture of 25 g. (0.1 mole) of 2-amino-5-chloro-2'-fluorobenzophenone,69.5 g. (1 mole) of hydroxylamine hydrochloride and 1 l. of pyridine wasstirred and heated overnight under reflux, and then concentrated invacuo. The residue was dissolved in ether and 10% sodium carbonatesolution. The organic phase was separated, washed with water three timesand with brine, dried over sodium sulfate and concentrated in vacuo togive 24 g. of an oil (crude oxime). A mixture of 24.0 g. of this oil,2.0 g. of anhydrous CuSO₄ and 250 ml. of acetone was heated and stirredunder reflux for 18 hours. The mixture was concentrated to dryness andthe residue was partitioned between CH₂ Cl₂ /H₂ O. The CH₂ Cl₂ waswashed with H₂ O (3x), dried over Na₂ SO₄, filtered and concentrated invacuo to give a crystalline residue. The residue was collected from Et₂O, mp 162°-165°. Recrystallization from aqueous MeOH gave yellow prisms,mp 163°-165°.

EXAMPLE 2 2-Amino-5-chloro-2'-fluorobenzophenone β-oxime

A mixture of 94.0 g. (0.308 mole) of6-chloro-2,2-dimethyl-4-(2-fluorophenyl)-1,2-dihydroquinazoline,3-oxide, and 2.3 l. of 3 N hydrochloric acid was stirred at roomtemperature for 3 hours. The solid was collected and then suspended inwater. This suspension was neutralized with sodium carbonate andextracted with methylene chloride. Concentration of the extracts leftcrude end product as a yellowish oil. TLC indicated a 9:1 mixture ofoxime and unreacted quinazoline. It was used as is in the subsequentreactions.

EXAMPLE 32-(Bromomethyl)-6-chloro-4-(2-fluorophenyl)-1,2-dihydroquinazoline-2-aceticacid ethyl ester 3-oxide

A solution of 17.5 g. (0.07 moles) of the product of Example 2, 48.1 g.of crude ethyl 4-bromoacetoacetate in 50 ml. of EtOH and 250 ml. ofethanol containing a few drops of 3 N aqueous HCl was boiled on asteambath for 1/4 hour, cooled and concentrated to a small volume. Theresidual mixture was partitioned between CH₂ Cl₂ and H₂ O. The CH₂ Cl₂was dried over Na₂ SO₄, filtered and concentrated in vacuo giving anamber oil. The oil was crystallized from Et₂ O/hexane giving crudeproduct, mp 105°-108° (dec.). Recrystallization from EtOAc/hexane gaveyellow prisms, mp 115°-117° (dec.).

EXAMPLE 42-(Bromomethyl)-6-chloro-4-(2-fluorophenyl)-1,2-dihydroquinazoline-2-aceticacid methyl ester, 3-oxide

A solution of 3.0 g. (0.01 moles) of6-chloro-2,2-dimethyl-4-(2-fluorophenyl)-1,2-dihydroquinazoline,3-oxide, 3.9 g. (0.02 moles) of methyl 4-bromoacetoacetate and 100 ml.of MeOH containing a few drops of 3 N aqueous HCl was boiled for 2hours. The mixture was diluted with several volumes of H₂ O andextracted with CH₂ Cl₂ (2 x). The CH₂ Cl₂ was dried over Na₂ SO₄,filtered and concentrated in vacuo to give an oil. The oil wascrystallized from Et₂ O/hexane to afford yellow prisms, mp 129°-133°(dec.). Recrystallization from CH₂ Cl₂ /hexane gave yellow prisms, mp132°-133° (dec.).

EXAMPLE 56-Chloro-2-(bromomethyl)-4-phenyl-1,2-dihydro-2-quinazolineacetic acid,ethyl ester, 3-oxide

A solution of 123.3 g. (0.52 moles) of 2-amino-5-chlorobenzophenone(β-oxime) 250 g. (1.2 moles) of crude ethyl 4-bromoacetoacetate in 250ml. of Et₂ O and 1.0 l. of EtOH was heated on a steambath for 1.4 hours.The solution was chilled on ice and the crystals collected to giveyellow prisms, mp 133°-135° (dec.). Recrystallization from CH₂ Cl₂/hexane afforded pure yellow prisms, mp 133°-135° (dec.).

EXAMPLE 62-(Bromomethyl)-6-chloro-4-phenyl-1,2-dihydroquinazoline-2-acetic acidmethyl ester, 3-oxide

A solution of 6.2 g. (0.025 moles) of 2-amino-5-chlorobenzophenone(β-oxime), 5.9 g. (0.030 moles) of methyl 4-bromoacetoacetate and 100ml. of MeOH containing a few drops of 3 N aqueous HCl was boiled for 1/2hour. The solution was cooled, diluted with several volumes of H₂ O andextracted with CH₂ Cl₂. The CH₂ Cl₂ extract was dried over Na₂ SO₄,filtered and concentrated in vacuo to give an oil. The oil wascrystallized from Et₂ O/hexane giving yellow prisms, mp 135°-138°(dec.). Recrystallization from EtOAc gave yellow prisms, mp 137°-138°(dec.).

EXAMPLE 7 6-Chloro-2-(chloromethyl)-4-phenyl-1,2-dihydro-2-quinazolineacetic acid, ethyl ester, 3-oxide

A mixture of 7.4 g. (0.03 moles) of 2-amino-5-chlorobenzophenone, 5.2 g.(0.033 moles) of ethyl 4-chloroacetoacetate and 75 ml. of EtOHcontaining 3 drops of 3 N aqueous HCl was heated on a steambath for 20minutes. The solution was chilled on ice and the crystals collected togive crude product, mp 140°-142° (dec.). Recrystallization from EtOHafforded yellow prisms, mp 143°-145° (dec.).

EXAMPLE 87-Chloro-5-(2-fluorophenyl)-1,2-dihydro-3H-1,4-benzodiazepine-2-ylideneacetic acid ethyl ester, 4-oxide

To a solution of 4.5 g. (0.01 mole) of the end product of Example 3 in100 ml. of ethanol was added 1.3 g. (0.012 mole) of potassiumt-butoxide. The solution was stirred at room temperature overnight andthen concentrated in vacuo. The residue was partitioned betweenmethylene chloride and water. The organic layer was washed with water,dried over sodium sulfate and concentrated in vacuo. The residue wasslurried with ether to give end product, mp 145°-150°. Recrystallizationfrom ethyl acetate/hexane gave off-white prisms, mp 148°-150° (dec.).

EXAMPLE 97-Chloro-5-(2-fluorophenyl)-1,2-dihydro-3H-1,4-benzodiazepin--ylideneacetic acid methyl ester, 4-oxide

To a stirred solution of 2.2 g. (0.05 moles) of the end product ofExample 4 in 100 ml. of MeOH 0.54 g. (0.01 moles) of NaOCH₃ was added.After 3/4 hour, the solution was diluted with H₂ O and extracted withCH₂ Cl₂. After drying and evaporation, an oil was obtained. The oil wastaken up CH₂ Cl₂ and filtered through a plug of silica gel eluting withCH₂ Cl₂. The eluates were concentrated to dryness and the residueslurried with Et₂ O to give analytically pure product as off-whiteprisms, mp 192°-193° (dec.).

EXAMPLE 10 7-Chloro-5-phenyl-2,3-dihydro-1H-benzodiazepin-1,4-2-ylideneacetic acid, ethyl ester, 4-oxide

To a solution of 1.3 g. (12 mmol) of potassium t-butoxide in 100 ml. ofethanol cooled to 5° was added 4.4 g. (10 mmole) of the end product ofExample 5. The ice bath was removed and the reaction mixture was stirredfor 1.5 hours while coming to room temperature. After concentration invacuo it was diluted with water, the pH was adjusted to 7 by addition ofacetic acid, and it was extracted with methylene chloride. The organicphase was washed with water, dried over sodium sulfate and concentratedin vacuo to leave 3.5 of tacky solid. This was slurried with ether togive crude product; mp 136°-138°. Recrystallization from ethylacetate/hexane gave off-white prisms, mp 138°-140°.

EXAMPLE 11 7-Chloro-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-ylideneacetic acid ethyl ester, 4-oxide

From 13.1 g. (30 mmole) of the end product of Example 5 treated withpotassium t-butoxide as above, there was obtained an oil, which showedtwo spots on TLC. This oil was chromatographed on 175 g. of silica gel.Elution with ethyl acetate gave the end product of Example 10, mp137°-140°. Elution with ethanol gave the desired end product aftercrystallization from ether. Recrystallization from ethanol gave yellowprisms, mp 186°-188°.

EXAMPLE 12 Conversion of 2-amino-5-chlorobenzophenone to7-chloro-5-phenyl-2,3-dihydro-1H-benzodiazepin-1,4,-2-ylidene aceticacid, ethyl ester, 4-oxide

A mixture of 7.4 g. (30 mmole) of 2-amino-5-chlorobenzophenone(β-oxime), 5.2 g. (33 mmole) of ethyl 4-chloroacetoacetate, 125 ml. ofethanol and 4 drops of 3 N hydrochloric acid was heated under refluxwith stirring for 0.5 hour. It was then cooled to 10° in an ice bath,and with stirring 60 ml. of 1 N sodium hydroxide was added. After 0.5hour, a white solid had precipitated. The reaction mixture was dilutedwith water and acidified to pH 6 with 3 N hydrochloric acid. The solidwas collected and washed with water to give the end product; mp140°-142° (dec.).

EXAMPLE 137-Chloro-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-ylideneaceticacid ethyl ester

Phosphorous trichloride, 10 ml., was added to a solution of 10 g.(0.0266 mol) of7-chloro-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-4-oxide-2-ylideneaceticacid ethyl ester in 100 ml. of methylene chloride. After standing atroom temperature for 3 hours, the reaction mixture was washed with 10%aqueous sodium carbonate solution. The methylene chloride layer wasseparated, dried over sodium sulfate and evaporated. This crude materialwas directly used for the next step. For the purpose of characterizationa sample was purified by filtering over a pad of silica gel using 10% ofethyl acetate in methylene chloride. Crystallization from ethanol gavecolorless crystals with mp 109°-111°.

EXAMPLE 147-Chloro-5-(2-chlorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-ylideneaceticacid ethyl ester

Phosphorus trichloride, 5 ml., was added to a solution of 7.8 g. (0.02mol) of7-chloro-5-(2-chlorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-4-oxide-2-ylideneaceticacid ethyl ester in 100 ml. of methylene chloride. After stirring atroom temperature for 11/2 hours, the solvent was evaporated underreduced pressure, at the end azeotropically with toluene. The residuewas partitioned between methylene chloride and 10% aqueous sodiumcarbonate solution. The organic layer was dried and evaporated to yieldcrude product which partially crystallized from 2-propanol. A portion ofthese crystals, 0.5 g., was recrystallized from methylenechloride/ethanol for analysis to give off-white crystals with mp103°-105°.

EXAMPLE 15

In the same fashion as Example 14 were prepared:

7-Chloro-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-ylideneaceticacid isopropyl ester.

Crystallized from 2-propanol, mp 144°-145°.

7-Chloro-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-ylideneaceticacid tert. butyl ester

Crystallized from hexane, mp 158°-160°.

EXAMPLE 167-Chloro-5-(2-fluorophenyl)-alpha-hydroxyimino-3H-1,4-benzodiazepine-2-aceticacid ethyl ester.

The crude7-chloro-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-ylideneaceticacid ethyl ester obtained by reduction of 10 g. of the end produce ofExample 15 as described above was dissolved in 40 ml. of glacial aceticacid. Sodium nitrite, 2.45 g., was added with stirring over a period of5 minutes. Following the addition the mixture was stirred at roomtemperature for 15 minutes. The product started to crystallize and wasfurther precipitated by addition of 50 ml. of water. The crystals werecollected, washed with water, ethanol and ether to yield the endproduct. The analytical sample was recrystallized fromtetrahydrofuran/ethanol to give pale yellow crystals with mp 230°-233°.

EXAMPLE 177-Chloro-5-(2-chlorophenyl)-alpha-hydroxyimino-3H-1,4-benzodiazepine-2-aceticacid ethyl ester.

Sodium nitrite, 1.5 g. (0.022 mol), was added to a solution of 6.2 g.crude7-chloro-5-(2-chlorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-ylideneaceticacid ethyl ester in 75 ml. of glacial acetic acid. After stirring atroom temperature for 20 minutes the reaction mixture was diluted with200 ml. of water. The precipitated product was collected, washed withwater and sucked dry to give crude product. The analytical sample wasrecrystallized from methylene chloride/ethanol to give light yellowcrystals with mp 219°-221°.

EXAMPLE 18

Similarly as in Example 17 there were obtained:

7-Chloro-5-(2-fluorophenyl)-alpha-hydroxyimino-3H-1,4-benzodiazepine-2-aceticacid isopropyl ester.

Crystallized from tetrahydrofuran/2-propanol, mp 244°-245° dec.

7-Chloro-5-(2-fluorophenyl)-alpha-hydroxyimino-3H-1,4-benzodiazepine-2-aceticacid tert.butyl ester.

Crystallized from methylene chloride/hexane, mp 212°-214°.

EXAMPLE 198-Chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylicacid, ethyl ester

(A) Phosphorus trichloride, 1 ml., was added to a solution of 1 g. (2.4mmol) of 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine-5-oxide-3-carboxylicacid, ethyl ester in 25 ml. of methylene chloride. After standing atroom temperature for 2 days, the solution was washed with 10% aqueoussodium carbonate solution, dried over sodium sulfate and evaporated.Crystallization of the residue from ether gave end product with mp174°-176°.

(B) A mixture of 0.5 g. (1.24 mmol) of7-chloro-5-(2-fluorophenyl)-alpha-hydroxyimino-3H-1,4-benzodiazepine-4-oxide-5-aceticacid ethyl ester 30 ml. of tetrahydrofuran, 10 ml. of ethanol and 0.25g. of 10% palladium on carbon was hydrogenated at atmospheric pressurefor 3 hours. A solution of acetaldehyde in tetrahydrofuran (10% v/v) wasthen added in three portions of 0.2 ml. at 1 hour intervals. After atotal reaction time of 6 hours the catalyst was filtered off and thefiltrate was evaporated. The residue was chromatographed over 7 g. ofsilica gel using methylene chloride/ethyl acetate 1:1. Crystallizationof the clean fractions from ether gave end product with mp 196°-198°after recrystallization from ethyl acetate/hexane.

EXAMPLE 208-Chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylicacid, isopropyl ester

(A) A mixture of 2 g. (5 mmol) of7-chloro-5-(2-fluorophenyl)-alpha-hydroxyimino-3H-1,4-benzodiazepine-2-aceticacid isopropyl ester, 50 ml, of tetrahydrofuran, 15 ml. of 2-propanol, 3g. of Raney nickel and 0.5 ml. of methanol containing 20% (v/v) ofammonia was hydrogenated at atmospheric pressure for 4 hours. Thecatalyst was filtered off and the filtrate was evaporated. The residuewas dissolved in 50 ml. of methylene chloride and treated with 0.6 ml ofacetaldehyde. After stirring at room temperature for 30 minutes 2 g. ofactivated manganese dioxide was added and stirring was continued foranother half hour. The MnO₂ was separated by filtration over Celite andthe filtrate was evaporated. Crystallization of the residue from ethergave end product in two crops. For analysis it was recrystallized fromethyl acetate, mp 200°-202°.

(B) This compound was also obtained by treatment of the correspondingN-oxide with phosphorus trichloride.

EXAMPLE 218-Chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylicacid tert.butyl ester

The product was obtained by hydrogenation of7-chloro-5-(2-fluorophenyl)-alpha-hydroxyimino-3H-1,4-benzodiazepine-2-aceticacid tert.butyl ester followed by oxidative condensation withacetaldehyde. It was crystallized from methylene chloride/hexane to givecolorless crystals with mp 215°-217°.

EXAMPLE 228-Chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylicacid

(A) A mixture of 0.15 g. (0.39 mmol) of8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine-5-oxide-3-carboxylicacid, 0.75 ml. of phosphorus trichloride and 25 ml. of methylenechloride was stirred at room temperature for 24 hours. The solvent wasremoved under reduced pressure and the residue was dissolved in 1 Nsodium hydroxide solution. The solution was then acidified with glacialacetic acid and extracted with methylene chloride. The extracts weredried and evaporated and the residue was crystallized frommethanol/ethyl acetate to yield colorless crystals with mp 272°-274°dec. (AW 7047/118)

(B) This compound was also obtained by alkaline hydrolysis of the ethylester of Example 19.

(C) This acid can also be prepared by alkaline hydrolysis of theisopropyl ester of Example 20 or by cleavage of the tert.butyl ester ofExample 21 with trifluoroacetic acid.

What is claimed:
 1. A process to produce a compound of the formula##STR5## wherein X and Y are selected from the group consisting ofhydrogen, halogen and trifluoromethyl and R₁ is hydrogen or lower alkylwhich comprises:(A) reacting a compound of the formula ##STR6## whereinX and Y are as above with a hydroxylamine salt at from 0° C. to about200° C. and thereafter reacting the resultant product with a lower alkylketone in the presence of a copper salt at from about room temperatureto reflux temperature (B) reacting the product of (A) with water in thepresence of a dilute strong acid at from about 0° C. to about 80° C. (C)reacting the product (A) or (B) with a compound of the formula ##STR7##wherein R₁ is as above and Z is a suitable leaving group at from aboutroom temperature to about 120° C. and (D) reacting the product of (C)with a base at from about -10° C. to about 100° C.